The following background discussion is provided to facilitate a better appreciation of the technology relating to the invention. As statements in this discussion may reflect viewpoints of an inventor, they should not be misconstrued as necessarily corresponding to knowledge in the prior art.
Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmitter eliciting effects via a multiplicity of receptors. To date, at least fifteen different 5-HT receptors have been identified (Marek et al., Neuropsychopharmacology (2003), 28:402-412), largely as the result of cloning cDNAs, and these receptors have been grouped into seven families (5-HT1 through 5-HT7) (Hoyer et al., Pharmacol. Biochem. Behav. (2002), 71:533-554). Fourteen of the fifteen cloned 5-HT receptors are expressed in the brain. Aberrant 5-HT availability or activity is implicated in various disease states, including: certain disorders of the central nervous system (CNS), such as depression, anxiety, schizophrenia, mood disorders, drug and alcohol dependence and addiction disorders; sleep disorders, jet lag, and sleep/wake disturbances; eating disorders; mood disorders; obsessive compulsive disorder; learning and memory dysfunction; migraine; chronic pain; temperature dysregulation; nociception; neurogenic inflammation; sexual dysfunction; cardiovascular disorders; vascular and hypertensive disorders; gastric disorders; irritable bowel disorders, urinary incontinence, hormone secretion, and cognition; and metabolic disorders. The identification of multiple 5-HT receptors has provided an opportunity to characterize existing therapeutic agents thought to act via the serotonergic system.
The 5-HT7 receptor is the most recently described member of the large family of serotonin receptors (see, e.g., Bard et al., J. Biol. Chem. (1993), 268(31):23422-23426; Hedlund et al., Trends in Pharmacol. Sci. (2004), 25(9):481-486; and Lovenberg et al., Neuron (1993), 11(3): 449-458). In the rodent and human brain, the highest receptor densities were found in the thalamus, hypothalamus (including the suprachiasmatic nucleus), amygdala, hippocampus, cortex and dorsal raphe (Bonaventure et al., Neuroscience (2004), 124(4):901-911; Thomas et al., Neuropharmacology (2002), 42(1):74-81; To et al., Br. J. Pharmacol. (1995), 115(1):107-116; and Varnas et al., Neurosci. Lett. (2004), 367(3):313-316). The 5-HT7 receptor has also been detected in the periphery, where it is found primarily in smooth muscle cells of blood vessels (Bard et al., J. Biol. Chem. (1993), 268(31):23422-23426), and in the gastrointestinal tract, where it is involved in peristalsis (Tuladhar et al., Br. J. Pharmacol. (2003), 138(7):1210-1214).
Recently discovered antagonists for the 5-HT7 receptor and knockout mice have been helpful for elucidating the receptor's role in several physiological and pathophysiological phenomena (see, e.g., Hedlund et al., Trends in Pharmacol. Sci. (2004), 25(9):481-486 and US Patent Application Publication No. 2005/0119295). Important functional roles for the 5-HT7 receptor have been established in thermoregulation, circadian rhythm, learning and memory, hippocampal signaling, sleep, and micturition (Glass et al., J. Neurosci. (2003), 23(20):7451-7460; Guscott et al., Neuropharmacology (2003), 44 (8):1031-1037; Hagan et al., Br. J. Pharmacol. (2000), 130(3):539-548; Hedlund et al., Proc. Natl. Acad. Sci. USA (2003), 100(3):1375-1380; Meneses, A., Behav. Brain Res. (2004), 155(2):275-282; and Read et al. IUPHAR Meeting (2002), San Francisco, Calif., USA).
The 5-HT7 receptor is implicated in circadian rhythm phase resetting, and two selective 5-HT7 receptor-selective antagonists (SB269970 and SB656104) have been shown to induce change in sleep parameters in a pattern opposite from those in patients with clinical depression. In wild type mice, SB269970 decreased immobility in both tail suspension and forced swim test, two tests used as predictor of antidepressant activity (Guscott et al. (2005), Neuropharmacology, 48(4):492-502; and Hedlund et al. (2005), Biol. Psychiatry, 58(10):831-837). When administered at the beginning of the sleep phase, both SB269970 and SB656104 increased the latency to rapid eye movement (REM) sleep and decreased the amount of time spent in REM sleep (Hagan et al., Br. J. Pharmacol. (2000), 130(3):539-548 and Thomas et al., Br. J. Pharmacol. (2003), 139(4):705-714). In addition, 5-HT7 knockout mice showed reduced immobility in both the forced swim and the tail suspension tests and spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressant like state (Hedlund et al., Biol. Psychiatry (2005), 58(10):831-837).
Some current treatments for depression exhibit considerable delay between start of treatment and subjective improvement. Many drugs do not cause an improvement in the Hamilton Rating Scale for Depression until after several weeks of treatment. Various drugs that are now available have a limited response rate and in some clinical trials only about 30% of patients show clinical improvement (Menza et al., J. Clin. Psych. (2000), 61:378-381). Psychiatrists frequently have to evaluate several drugs for individual patients before a satisfactory therapeutic response is observed.
Current clinical treatment of depression typically involves a drug selected from one of four types of drugs: 1) monoamine oxidase (MAO) inhibitors; 2) tricyclic antidepressants (TCA); 3) selective serotonin reuptake inhibitors (SSRIs); and 4) other drugs such as reboxetine and venlafaxine. MAOs have long been used as second-line drugs because of their potentially dangerous side effects; but more recently, reversible MAO-A selective inhibitors with improved profiles have been described (Bonnet, CNS Drug Reviews (2002), 8:283-308). TCAs such as amitryptiline display complex pharmacological activities. They inhibit reuptake of noradrenaline and serotonin via their respective transporters, but also have affinity at muscarinic and histamine H1 receptors. Thus, their efficacy in treating depression is counterbalanced by numerous unwanted side effects. The SSRIs, which represent a large and successful class of antidepressants (see, e.g., Spinks, Current Med. Chem. (2002), 9:799-810), show a higher selectivity for the serotonin transporter (SERT) than for the norepinephrine transporter (NET), although the exact affinity ratio varies from drug to drug. This class of drugs is typically characterized by a milder side-effect profile than the MAO-inhibitors or the TCAs. Other drugs have been described, such as reboxetine, which preferentially targets the NET, and venlafaxine, which has dual activity at the SERT and NET (Olver et al., CNS Drugs (2001), 15: 941-954).
Although progress has been made in the treatment of various diseases and disorders associated with aberrant 5-HT function, there remains a desire for improved therapies.